HERPES SIMPLEX VIRUS INFECTION

Herpes virus causes one of the most widespread viral infections. The primary infection usually occurs in a child younger than 6 years of age who has had no contact with the type 1 herpes simplex virus (HSV-1) and who therefore has no neutralizing antibodies. It is believed that 99% of all primary infections are of the subclinical type. The infection may also occur in susceptible adults who have not had a primary infection (Fig. 20-4).

Figure 20-4 Ulcerated stage of primary herpes in a young adult. Notice the circumscribed confluent areas of inflammation.

In some preschool children the primary infection may be characterized by only one or two mild sores on the oral mucous membranes, which may be of little concern to the child or may go unnoticed by the parents. In other children, the primary infection may be manifested by acute symptoms (acute herpetic gingivostomatitis). The active symptoms of the acute disease can occur in children with clean mouths and healthy oral tissues. In fact, these children seem to be as susceptible as those with poor oral hygiene. The symptoms of the disease develop suddenly and include, in addition to the fiery red gingival tissues, malaise, irritability, headache, and pain associated with the intake of food and liquids of acid content. A characteristic oral finding in the acute primary disease is the presence of yellow or white liquid-filled vesicles. In a few days the vesicles rupture and form painful ulcers, 1 to 3 mm in diameter, which are covered with a whitish gray membrane and have a circumscribed area of inflammation (Figs. 20-5 and 20-6). The ulcers may be observed on any area of the mucous membrane, including buccal mucosa, tongue, lips, hard and soft palate, and the tonsillar areas. Large ulcerated lesions may occasionally be observed on the palate or gingival tissues or in the region of the mucobuccal fold. This distribution makes the differential diagnosis more difficult. An additional diagnostic criterion is a fourfold rise of serum antibodies to HSV-1. The lesion culture also shows positive results for HSV-1.

Figure 20-5 A, Acute herpetic gingivostomatitis in an 18-month-old child. The fiery red gingival tissues and the presence of ulcers on the mucous membrane are characteristic findings. B, Considerable improvement is evident within a week after the occurrence of the acute symptoms. C, Symptoms of the disease have subsided in 2 weeks. Mild inflammation of isolated gingival papillae is still evident.

Figure 20-6 Several large, painful ulcers are evident on the tongue of a preschool child with acute herpetic gingivostomatitis.

Treatment of acute herpetic gingivostomatitis in children, which runs a course of 10 to 14 days, should include specific antiviral medication as well as provision for the relief of the acute symptoms so that fluid and nutritional intake can be maintained. The application of a mild topical anesthetic, such as dyclonine hydrochloride (0.5%) (Dyclone) before mealtime temporarily relieves the pain and allows the child to take in soft food. Another topical anesthetic, lidocaine (Xylocaine Viscous), can be prescribed for the child who can hold 1 teaspoon of the anesthetic in the mouth for 2 to 3 minutes and then expectorate the solution. Schaaf recommends as an alternative to the anesthetic a mixture of equal parts of diphenhydramine (Benadryl) elixir and Kaopectate.¹¹ This material can be compounded by the pharmacist or mixed by the parent. The diphenhydramine has mild analgesic and antiinflammatory properties, whereas the kaolin-pectin compound coats the lesions. Because fruit juices are usually irritating to the ulcerated area, ingestion of a vitamin supplement during the course of the disease is indicated.

Although the treatments described may be useful, they are only palliative. The mainstay of definitive therapy is regular doses of specific systemic antiviral medication combined with systemic analgesics (acetaminophen or ibuprofen) during the course of the disease.¹² The antiviral medications currently available are acyclovir, famciclovir, and valacyclovir. These medications inhibit viral replication in cells infected with the virus. Acyclovir (Zovirax; GlaxoSmithKline, Inc., Research Triangle Park, NC) should be administered in five daily doses to equal 1000 mg per day for 10 days. Acyclovir is available in capsules or suspension. Acyclovir therapy has been successfully used in infants and children.¹³ Famciclovir (Famvir; Novartis Pharmaceuticals Corporation, East Hanover, NJ) and valacyclovir (Valtrex; GlaxoSmithKline, Inc., Research Triangle Park, NC) are newer and possibly more effective antiviral agents, but their use in pediatric populations has not yet been studied. Food and Drug Administration (FDA) approved treatment for recurrent herpes simplex labialis (cold sore, fever blister) in children 12 years and older is valacyclovir 2 g, initially and 2 g 12 hours later. Famciclovir 1500 g one dose with prodrome (earliest sign of the lesions) is a FDA-approved treatment for herpes simplex labialis in adults, but it has not been studied in children. Bed rest and isolation from other children in the family are also recommended. Hale and colleagues reported an outbreak of herpes simplex infection in a group of 13 children occupying one floor in an orphanage.¹⁴ The children ranged in age from 11 to 35 months. In three of the children, a mild fever of brief duration and small oral lesions were the only signs of infection; these might easily have been unobserved in a situation different from that of an institutional study. The remaining children had symptoms of acute infection.

After the initial primary attack during early childhood, the herpes simplex virus becomes inactive and resides in sensory nerve ganglia. The virus often reappears later as the familiar cold sore or fever blister, usually on the outside of the lips (Fig. 20-7). Thus the disease has been commonly referred to as recurrent herpes labialis (RHL). However, approximately 5% of recurrences are intraoral. With the recurring attacks, the sores develop in essentially the same area. Kleinman and colleagues published the results of a national survey of 39,206 schoolchildren aged 5 to 17 years.¹⁵ A history of RHL was reported by 33% of the children.

Figure 20-7 Recurrent herpes labialis. A, Early vesicular lesions. B, Mature vesicular lesion. C, Appearance of herpes labialis after rupture of vesicles and crusting of the lesion.

(A, B, and C Courtesy of Dr. Susan L. Zunt.)

The recurrence of the disease has often been related to conditions of emotional stress and lowered tissue resistance resulting from various types of trauma. Excessive exposure to sunlight may be responsible for the appearance of the recurrent herpetic lesions on the lip. Use of sunscreen can prevent sun-induced recurrences. Lesions on the lip may also appear after dental treatment and may be related to irritation from rubber dam material or even routine daily procedures.

The most effective treatment for these recurrences is the use of the specific systemic antiviral medications already discussed in connection with the treatment of the primary herpetic infection (acyclovir, famciclovir, and valacyclovir).¹² The medication should be taken immediately after the prodromal symptom of recurrence. The daily dosages are the same as those for the primary infection, but the course of treatment is usually 5 days instead of 10. One-day therapy for recurrent herpes labialis is a total of 4 g valacyclovir given in a divided dose; 2 g initially with the prodrome, followed 12 hours later with another 2 g. This regimen has been approved for children 12 years of age and older. Another topical antiviral agent, penciclovir cream (Denavir; Novartis Consumer Health, Inc., Parsippany, NJ), may be applied to perioral lesions but should not be applied to intraoral lesions. The penciclovir cream and systemic antivirals should not be prescribed for concurrent use. The penciclovir cream can be applied every 2 hours while awake for 4 days, and it is approved for use in children 12 years of age and older. Topical 5% acyclovir cream may be prescribed for use five times daily for 4 days in children 12 years of age and older.

Other remedies for herpes simplex infection also include the amino acid lysine. The oral therapy is based on lysine’s antagonistic effect on another amino acid, arginine. Griffith and associates conducted an initial study in which 250 patients were given daily lysine doses of 1000 mg and were told to avoid eating arginine-rich foods, such as chocolate and nuts.¹⁶ The lysine therapy was continued until the patients had been lesion free for 6 months. l-Lysine monohydrochloride is available commercially in capsule form or tablets containing 100 or 312 mg of l-Lysine (General Nutrition Corp., Pittsburgh, Pa.). The patients reported that pain disappeared overnight in virtually every instance. New vesicles failed to appear, and a majority considered the resolution of the lesions to be more rapid than in the past. There was also a reduction in frequency of occurrences. Griffith and colleagues concluded that improper food selection may make adequate lysine intake precarious for some persons.¹⁶ Ingestion of cereals, seeds, nuts, and chocolate would produce a high arginine/lysine ratio and favor the development of herpetic lesions. Similar results are obtained when arginine is added to the medium in the laboratory to induce herpes proliferation. The avoidance of these foods, coupled with the selection of foods with adequate lysine, such as dairy products and yeast, should discourage herpes infection. These authors postulate that this may explain the low incidence of herpes in infants before they are weaned from a predominantly milk diet. Prophylactic lysine is apparently useful in managing selected cases of RHL if serum lysine is maintained at adequate concentrations.

Brooks and associates have reported that dentists are frequently exposed to HSV-1.¹⁷ They evaluated the risk of infection with the virus by assessing disease experience, comparing the individual’s history with the results of a complement fixation or antibody titration test, or both. Their study group consisted of 525 dental students, 94 dental faculty members, and 23 staff members. Although almost all of those with a history of herpetic infection showed antibodies to HSV-1, only 57% of those lacking such a history had neutralizing antibody titers of 1:10 or higher. This finding suggests that a significant portion of practicing dentists risk primary herpetic infection. Consequently, dentists and dental auxiliaries without a history of herpetic lesions might benefit from serologic testing. Considering the occupational disability that often accompanies HSV-1 infection of the finger or eye, effective barrier protection for health professionals is important.

Primary herpetic infection has been observed on the dorsal surface of the thumb of a pediatric patient (Fig. 20-8). The child was a thumb sucker, and the acute primary infection was present in the mouth. The dorsal surface of the thumb, which rested on the lower incisor teeth, apparently became irritated, and an inoculation of the virus took place. The oral condition and the lesions on the thumb subsided in 2 weeks.

Figure 20-8 Primary herpetic infection involving the dorsal surface of the thumb of a 3-year-old child. An acute primary infection was present in the mouth.

RECURRENT APHTHOUS ULCER (CANKER SORE)

The recurrent aphthous ulcer (RAU)—also referred to as recurrent aphthous stomatitis (RAS)—is a painful ulceration on the unattached mucous membrane that occurs in school-aged children and adults. The peak age for RAU is between 10 and 19 years of age. It has been reported to be the most common mucosal disorder in people of all ages and races in the world. This disorder, according to definitions adopted in the epidemiologic literature, is characterized by recurrent ulcerations on the moist mucous membranes of the mouth, in which both discrete and confluent lesions form rapidly in certain sites and feature a round to oval crateriform base, raised reddened margins, and pain. They may appear as attacks of minor or single, major or multiple, or herpetiform lesions. They may or may not be associated with ulcerative lesions elsewhere.¹⁸ In the national survey reported by Kleinman and colleagues, a history of RAU was reported by 37% of the schoolchildren and occurred approximately three times more often in white than in black schoolchildren.¹⁵ Ship and colleagues reported the prevalence estimates of RAU to range between 2% and 50% with most estimates between 5% and 25% (among medical and dental students, estimated prevalence is between 50% and 60%).¹⁹ Lesions persist for 4 to 12 days and heal uneventfully, leaving scars only rarely and only in cases of unusually large lesions. The description of RAU frequently includes the term canker sores (Fig. 20-9). The major form (RAS) is less common and has been referred to as periadenitis mucosa necrotica recurrens and Sutton disease. RAS has been associated with other systemic diseases: PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis), Behçet disease, Crohn disease, ulcerative colitis, celiac disease, neutropenia, immunodeficiency syndromes, Reiter syndrome, systemic lupus erythematosus, and MAGIC (mouth and genital ulcers with inflamed cartilage) syndrome.

Figure 20-9 A, Evidence of the development of a recurrent aphthous ulcer in the mucobuccal fold above the primary canine. An area of inflammation and vesicle formation is apparent (arrow). B, Five days later the lesion is a well-developed ulcer with a circumscribed area of inflammation.

The cause of RAU is unknown. Local and systemic conditions along with a genetic predisposition, as well as immunologic and infectious microbial factors, have been identified as potential causes. The condition may be caused by a delayed hypersensitivity to the L form of Streptococcus sanguis, which is a common constituent of the normal oral microbiota of humans. It is also possible that the lesions are caused by an autoimmune reaction of the oral epithelium. Epidemiologic studies by Ship and colleagues provide evidence for this hypothesis.¹⁹ These data indicate that both RHL and RAU may be produced by the same mechanism, despite the known infectious agent of RHL and the absence of any known virus for RAU. Scully and Porter reported strong associations with interleuken genotypes.¹⁸

Local factors include trauma, allergy to toothpaste constituents (sodium lauryl sulfate), and salivary gland dysfunction. In a review of the clinical problem, Antoon and Miller suggested that minor trauma is a common precipitating factor accounting for as many as 75% of the episodes.²⁰ Injuries caused by cheek biting and minor facial irritations are probably the most common precipitating factors. Nutritional deficiencies are found in 20% of persons with aphthous ulcers. The clinically detectable deficiencies include deficiencies of iron, vitamin B₁₂, and folic acid. While screening patients with aphthous ulcers, Wray and associates observed a history of unusually high incidence of gastrointestinal disorders.²¹ Stress may prove to be an important precipitating factor, particularly in stress-prone groups, such as students in professional schools and military personnel.

According to Greenspan and colleagues, either nonspecific factors (trauma, food allergy) or specific factors (bacterial or viral infection) may trigger a temporary imbalance in various cell subpopulations.²² This imbalance could then upset immune regulation and result in local destruction of the oral epithelium and thus ulceration. Ship and colleagues also suggested herpes simplex virus, human herpesvirus type 6, cytomegalovirus, Epstein-Barr virus, and varicella-zoster virus as possible causes of RAS.¹⁹

Current treatment is focused on promoting ulcer healing, reducing ulcer duration and patient pain, maintaining the patient’s nutritional intake, and preventing or reducing the frequency of recurrence of the disease.

A variety of treatments have been recommended for RAU, but a completely successful therapy has not been found. Topical antiinflammatory and analgesic medicines and/or systemic immunomodulating and immunosuppression agents have been used for RAU. The primary line of treatment uses topical gels, creams, and ointments as antiinflammatory agents. Currently, a topical corticosteroid (e.g., 0.5% fluocinonide, 0.025% triamcinolone, 0.5% clobetasol) is applied to the area with a mucosal adherent (e.g., isobutyl cyanoacrylate, Orabase). For example, the application of triamcinolone acetonide (Kenalog in Orabase) to the surface of the lesions before meals and before sleeping may also be helpful. Binnie and colleagues reported that an antiinflammatory and antiallergic medication in the form of a topical paste is effective in reducing pain and accelerating healing of RAU ulcers.²³ The active ingredient in the paste is 5% amlexanox and it is available under the trade name Aphthasol (Access Pharmaceuticals, Dallas, Texas). The paste is applied to the ulcer four times daily, after meals and at bedtime, until the ulcer heals. Zilactin (Zila Pharmaceuticals, Phoenix, Ariz), a topical paste with hydroxypropyl cellulose film, has also been used to adhere to the mucosa and cover the ulcer while providing pain relief for an extended period of time. Occlusive topical 2-otylcyanoacrylate adheres for 6 hours. Aloe vera freeze-dried gel extract adheres and forms an occlusive protective patch. In severe cases, oral prednisone has been prescribed.

Topical rinses have also been helpful for relief of RAU. Sucralfate has proved useful by coating the area. The topical application of tetracycline to the ulcers is often helpful in reducing the pain and in shortening the course of the disease. A mouthwash containing suspension of one of the tetracyclines has been helpful to some, but the mouthwash should not be swallowed. Chlorhexidine mouthwash has also been known to alleviate the symptoms of RAU. Swished dexamethasone elixir is useful to treat ulcerations in areas of the mouth that are difficult to access. Other findings that may be of significance include those of the two following studies: Meiller and associates have reported that the duration and severity of RAU lesions can be significantly reduced by vigorous twice-daily rinsing with an antimicrobial mouthwash (Listerine Antiseptic, Pfizer Warner Lambert Division, Morris Plains, NJ).²⁴ Pedersen reported that some of her recent work suggests that varicella-zoster virus may be of etiologic importance in RAU.²⁵ Furthermore, she found that six of eight patients with chronic severe RAU who were treated with acyclovir responded favorably within 2 days.

ACUTE NECROTIZING ULCERATIVE GINGIVITIS (VINCENT INFECTION)

The infectious disease commonly referred to as acute necrotizing ulcerative gingivitis (ANUG) is rare among preschool children in the United States, occurs occasionally in children 6 to 12 years old, and is common in young adults. Reade reported one instance of the typical picture of ulcerative gingivitis in a 15-month-old infant.²⁶ Treponema vincentii and gram-negative fusiform bacilli were demonstrated in a smear. Recovery occurred within 36 hours after initiation of penicillin therapy and the application of hydrogen peroxide.

ANUG can be easily diagnosed because of the involvement of the interproximal papillae and the presence of a pseudomembranous necrotic covering of the marginal tissue (Fig. 20-10). Two microorganisms, Borrelia vincentii and fusiform bacilli, referred to as spirochetal organisms, are generally believed to be responsible for the disease. The clinical manifestations of the disease include inflamed, painful, bleeding gingival tissue, poor appetite, temperature as high as 40°C (104°F), general malaise, and a fetid odor.

Figure 20-10 A, A rare example of necrotizing ulcerative gingivitis in an 8-year-old boy. B, Local treatment and improved oral hygiene produced a dramatic recovery from the infection.

The disease responds dramatically within 24 to 48 hours to subgingival curettage, débridement, and the use of mild oxidizing solutions. If the gingival tissues are acutely and extensively inflamed when the patient is first seen, antibiotic therapy is indicated. Improved oral hygiene, the use of mild oxidizing mouth rinses after each meal, and twice-daily rinsing with chlorhexidine will aid in overcoming the infection.

There should be no difficulty in distinguishing ANUG from acute herpetic gingivostomatitis, although the two are sometimes confused. Round ulcers with red areolae on the lips and cheeks are characteristic of herpetic gingivostomatitis. Therapeutic prophylaxis and débridement bring about a favorable response in cases of ANUG but not in acute herpetic gingivostomatitis. A therapeutic trial of antibiotics reduces the acute symptoms in ANUG but not in the viral infection. Acute herpetic gingivostomatitis is most frequently seen in preschool children, and its onset is rapid. As stated earlier, ANUG rarely occurs in the preschool-aged group and develops over a longer period, usually in a mouth in which irritants and poor oral hygiene are present. On the other hand, acute oral infections initially diagnosed as ANUG have frequently been found later to be an oral manifestation of one of the xanthomatoses. The early stages of conditions such as Hand-Schüller-Christian disease and Letterer-Siwe disease are associated with many of the symptoms of ANUG.

ACUTE CANDIDIASIS (THRUSH, CANDIDOSIS, MONILIASIS)

Candida (Monilia) albicans is a common inhabitant of the oral cavity but may multiply rapidly and cause a pathogenic state when host resistance is lowered. Young children sometimes develop thrush after local antibiotic therapy, which allows the fungus to proliferate. The lesions of the oral disease appear as raised, furry, white patches, which can be removed easily to produce a bleeding underlying surface (Fig. 20-11). Neonatal candidiasis, contracted during passage through the vagina and erupting clinically during the first 2 weeks of life, is a common occurrence. This infection is also common in immunosuppressed patients (see Chapter 24).

Figure 20-11 A, The characteristic appearance of acute candidiasis on the upper and lower lips of a young patient. The hard and soft palates were also severely affected. B, The infection was controlled with a 7-day regimen of nystatin.

Antifungal antibiotics control thrush. For infants and very young children, a suspension of 1 mL (100,000 U) of nystatin (Mycostatin) may be dropped into the mouth for local action four times a day. The drug is nonirritating and nontoxic. Clotrimazole suspension (10 mg/mL), 1 to 2 mL applied to affected areas four times daily, is an effective antifungal medication. Systemic fluconazole suspension (10 mg/mL) is safe to use in infants at a total dosage of 6 mg/kg or less per day. For children old enough to manage solid medication allowed to dissolve in the mouth, clotrimazole troches or nystatin pastilles are recommended, because the therapeutic agent remains in the saliva longer than with the liquid medication. For children old enough to swallow, systemic fluconazole (100-mg tablets) in a 14-day course may be prescribed for patients whose infection has not responded to topical antifungal agents.

ACUTE BACTERIAL INFECTIONS

The prevalence of acute bacterial infection in the oral cavity is unknown. Blake and Trott reported acute streptococcal gingivitis with painful, vivid red gingivae that bled easily.²⁷ The papillae had enlarged, and gingival abscesses had developed. Cultures showed a predominance of hemolytic streptococci. Acute infections of this type may be more common than was previously realized. Littner and associates reported five cases, all in adults between 20 and 27 years of age.²⁸ The diagnosis is difficult to make, however, without extensive laboratory tests. Broad-spectrum antibiotics are recommended if the infection is believed to be bacterial in origin. Improved oral hygiene is important in treating the infection. As with any acute microbial oral infection, chlorhexidine mouth rinses are also appropriate. The placement of dental restorations to restore adequate function and contour after the reduction of acute symptoms is equally important.

GINGIVAL DISEASES ASSOCIATED WITH THE ENDOCRINE SYSTEM

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